The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
Open accessAbstract
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes. METHODS: We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m(2), HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry. RESULTS: Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol • min(-1) • m(-2) • mM(-1) and 55 [IQR, 39] pmol • min(-1) • m(-2) • mM(-1) vs. 44 [IQR, 32] pmol • min(-1) • m(-2) • mM(-1), P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged. CONCLUSIONS: In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid. Trial registration. ClinicalTrials.Gov NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study was funded by Boehringer Ingelheim.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Previous RCTs reported that selective SGLT2 inhibitors, a new class of anti-diabetes drugs, have been shown to reduce body weight (1–3 kg reduction) in diabetic patients with and without obesity [99–102].”
From Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? (2021) · cites this paper as [99]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The theoretical bases of indirect calorimetry: A review
Ferrannini, E. (1988) · Metabolism · doi:10.1016/0026-0495(88)90110-2 · Cited by 1,604
Self-citationWatson, P. E., Watson, I. D., & Rd, B. (1980) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/33.1.27 · Cited by 1,477
Biology of Human Sodium Glucose Transporters
Wright, E. M., Loo, D. D. F., & Hirayama, B. A. (2011) · Physiological Reviews · doi:10.1152/physrev.00055.2009 · Cited by 1,430
Effect of fatty acids on glucose production and utilization in man.
Ferrannini, E., Barrett, E. J., Bevilacqua, S., & DeFronzo, R. A. (1983) · Journal of Clinical Investigation · doi:10.1172/jci111133 · Cited by 1,050
Self-citationINDOCYANINE GREEN: OBSERVATIONS ON ITS PHYSICAL PROPERTIES, PLASMA DECAY, AND HEPATIC EXTRACTION*
Cherrick, G. R., Stein, S. W., Leevy, C. M., & Davidson, C. S. (1960) · Journal of Clinical Investigation · doi:10.1172/jci104072 · Cited by 978
Sodium–Glucose Cotransporter 2 Inhibitors for Type 2 Diabetes: A Systematic Review and Meta-analysis
Vasilakou, D., Karagiannis, T., Athanasiadou, E., Mainou, M., Liakos, A., Bekiari, E., Sarigianni, M., Matthews, D. R., & Tsapas, A. (2013) · Annals of Internal Medicine · doi:10.7326/0003-4819-159-4-201308200-00007 · Cited by 911
Cauter, E. V., Mestrez, F., Sturis, J., & Polonsky, K. S. (1992) · Diabetes · doi:10.2337/diab.41.3.368 · Cited by 887
Rossetti, L., Smith, D. J., Shulman, G. I., Papachristou, D. N., & DeFronzo, R. A. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112981 · Cited by 824
SGLT2 Mediates Glucose Reabsorption in the Early Proximal Tubule
Vallon, V., Platt, K. A., Cunard, R. A., Schroth, J., Whaley, J. M., Thomson, S. C., Koepsell, H., & Rieg, T. (2010) · Journal of the American Society of Nephrology · doi:10.1681/asn.2010030246 · Cited by 565
Bolinder, J., Ljunggren, Ö., Johansson, L. O. M., Wilding, J. P. H., Langkilde, A., Sjöström, C. D., Sugg, J. E., & Parikh, S. J. (2013) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12189 · Cited by 492
Flagged first, then by citations
Research works printed but not linked: 1
- Yki-Järvinen, 1992, Endocr Rev., 13, 415
Cited by
Sorted by citations
Items 101–200 of 999
The Role of Glucagon in the Pathophysiology and Treatment of Type 2 Diabetes
Hædersdal, S., Lund, A., Knop, F. K., & Vilsbøll, T. (2018) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2017.12.003 · Cited by 162
“In the other study, Ferrannini et al(168) reported that patients exhibited glycosuria after empagliflozin treatment, but empagliflozin was also associated with increased endogenous glucose production, beta-cell glucose sensitivity, and postprandial glucagon response.(168) Notably, studies measuring glucagon are often…”
BackgroundResultAntihypertensive and Renal Mechanisms of SGLT2 (Sodium-Glucose Linked Transporter 2) Inhibitors
Wilcox, C. S. (2020) · Hypertension · doi:10.1161/hypertensionaha.119.11684 · Cited by 167
“Glycosuria causes a negative calorie balance although this is offset by hyperphagia.(24) SGLT2is switch”
BackgroundButler, J., HAMO, C. E., Filippatos, G. S., Pocock, S., Bernstein, R. A., Brueckmann, M., Cheung, A. K., George, J. T., Green, J. B., Januzzi, J. L., et al. (2014) · European Journal of Heart Failure · doi:10.1002/ejhf.933 · Cited by 167
Self-citationLahnwong, C., Chattipakorn, S. C., & Chattipakorn, N. (2018) · Cardiovascular Diabetology · doi:10.1186/s12933-018-0745-5 · Cited by 160
SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits
Preda, A., Montecucco, F., Carbone, F., Camici, G. G., Lüscher, T. F., Kraler, S. C., & Liberale, L. (2024) · Cardiovascular Research · doi:10.1093/cvr/cvae047 · Cited by 210
Revisiting the role of glucagon in health, diabetes mellitus and other metabolic diseases
Hædersdal, S., Andersen, A., Knop, F. K., & Vilsbøll, T. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00817-4 · Cited by 168
Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion
Vergari, E., Knudsen, J. G., Ramracheya, R., Salehi, A., Zhang, Q., Adam, J., Asterholm, I. W., Benrick, A., Briant, L. J. B., Chibalina, M. V., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-08193-8 · Cited by 152
Empagliflozin: A Review in Type 2 Diabetes
Frampton, J. E. (2018) · Drugs · doi:10.1007/s40265-018-0937-z · Cited by 156
“Induced glycosuria in both the fasting and fed state and improved β-cell function and insulin sensitivity [72, 73].”
BackgroundMathieu, C., Ranetti, A.-E., Li, D., Ekholm, E., Cook, W., Hirshberg, B., Chen, H., Hansen, L., & Iqbal, N. (2015) · Diabetes Care · doi:10.2337/dc15-0779 · Cited by 151
“in a lessening of glucotoxicity (32,33) that relieves some of the burden on the failing b-cells.”
Glucose transporters in the kidney in health and disease
Vallon, V. (2020) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-020-02361-w · Cited by 152
Obata, A., Kubota, N., Kubota, T., Iwamoto, M., Satō, H., Sakurai, Y., Takamoto, I., Katsuyama, H., Suzuki, Y., Fukazawa, M., et al. (2015) · Endocrinology · doi:10.1210/en.2015-1588 · Cited by 143
Gallo, L. A., Ward, M. S., Fotheringham, A. K., Zhuang, A., Borg, D. J., Flemming, N., Harvie, B. M., Kinneally, T. L., Yeh, S.-M., McCarthy, D. A., et al. (2016) · Scientific Reports · doi:10.1038/srep26428 · Cited by 143
Rosenstock, J., Chuck, L. H. S., González-Ortı́z, M., Merton, K., Craig, J., Capuano, G. A., & Qiu, R. (2016) · Diabetes Care · doi:10.2337/dc15-1736 · Cited by 143
“In contrast, dapagliflozin and empagliflozin have both been associated with an increase in EGP that has been attributed to increased plasma glucagon levels (38,39).”
BackgroundCurrent and emerging avenues for Alzheimer's disease drug targets
Loera‐Valencia, R., Cedazo-Mínguez, Á., Kenigsberg, P.-A., Page, G., Duarte, A. I., Giusti, P., Zusso, M., Robert, P. H., Frisoni, G. B., Cattaneo, A., et al. (2019) · Journal of Internal Medicine · doi:10.1111/joim.12959 · Cited by 142
β-Cell function in type 2 diabetes
Ferrannini, E., & Mari, A. (2014) · Metabolism · doi:10.1016/j.metabol.2014.05.012 · Cited by 153
“modification [74], glucose-lowering drug therapywithmetformin [75], sulfonylureas [75], glinides [76], thiazolidinediones [75],GLP-1 receptor agonists [77], DPP-4 inhibitors [78], sodium-glucose cotransporter-2 inhibitors [79], insulin [80], restrictive [81] or”
BackgroundSelf-citationSGLT2 Inhibition for the Prevention and Treatment of Diabetic Kidney Disease: A Review
Alicic, R. Z., Johnson, E. J., & Tuttle, K. R. (2018) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2018.03.022 · Cited by 136
García‐Ropero, Á., Badimón, J. J., & Santos‐Gallego, C. G. (2018) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2018.1551877 · Cited by 150
“Of note, empagliflozin-induced glycosuria reduces both plasma glucose and insulin levels while increases both lipolysis and plasma glucagon concentration, which causes ketogenesis and hyperketonemia [101,102]; this pattern is similar to that of fasting except that fasting develops slower.”
BackgroundSGLT2 Inhibitors: The Star in the Treatment of Type 2 Diabetes?
Saisho, Y. (2020) · Diseases · doi:10.3390/diseases8020014 · Cited by 145
“On the other hand, glucagon secretion increases after administration of SGLT2 inhibitors, possibly because of rapid loss of glucose from the body [23,24].”
BackgroundOrgan protection by SGLT2 inhibitors: role of metabolic energy and water conservation
Marton, A., Kaneko, T., Kovalik, J., Yasui, A., Nishiyama, A., Kitada, K., & Titze, J. M. (2020) · Nature Reviews Nephrology · doi:10.1038/s41581-020-00350-x · Cited by 136
Emergence of SGLT2 Inhibitors as Powerful Antioxidants in Human Diseases
Tsai, K., Chen, Y., Chiou, T. T., Chu, T., Li, L., Ng, H., Lee, W., & Lee, C. (2021) · Antioxidants · doi:10.3390/antiox10081166 · Cited by 140
Durante, W., Behnammanesh, G., & Peyton, K. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168786 · Cited by 135
Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy
Angelidi, A. M., Belanger, M. J., Kokkinos, A. D., Koliaki, C. C., & Mantzoros, C. S. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab034 · Cited by 141
The Biology of Glucagon and the Consequences of Hyperglucagonemia
Albrechtsen, N. J. W., Kuhre, R. E., Pedersen, J., Knop, F. K., & Holst, J. J. (2016) · Biomarkers in Medicine · doi:10.2217/bmm-2016-0090 · Cited by 132
On behalf of the EMPA-REG EXTEND™ MONO investigators, Roden, M., Merker, L., Christiansen, A. V., Roux, F., Salsali, A., Kim, G., Stella, P., Woerle, H. J., & Broedl, U. C. (2015) · Cardiovascular Diabetology · doi:10.1186/s12933-015-0314-0 · Cited by 128
“In accordance with its insulin-independent mode of action [30], and the results of previous studies, Table 3 Adverse events”
ResultSelf-citationGlucagon – Early breakthroughs and recent discoveries
Åhrén, B. (2015) · Peptides · doi:10.1016/j.peptides.2015.03.011 · Cited by 129
SGLT2 Inhibitors and Their Mode of Action in Heart Failure—Has the Mystery Been Unravelled?
Pabel, S., Hamdani, N., Luedde, M., & Sossalla, S. T. (2021) · Current Heart Failure Reports · doi:10.1007/s11897-021-00529-8 · Cited by 142
Takeshita, Y., Honda, M., Harada, K., Kita, Y., Takata, N., Tsujiguchi, H., Tanaka, T., Goto, H., Nakano, Y., Iida, N., et al. (2022) · Diabetes Care · doi:10.2337/dc21-2049 · Cited by 131
“In the tofogliflozin group, genes involved in gluconeogenesis were coordinately upregulated, consistent with clinical observations in which the SGLT2 inhibitor is associated with an elevated endogenous glucose production (48,49).”
ResultKidney-Protective Effects of SGLT2 Inhibitors
Palmer, B. F., & Clegg, D. J. (2022) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.09380822 · Cited by 128
Hundertmark, M., Adler, A., Antoniades, C. A., Coleman, R. L., Griffin, J. L., Holman, R. R., Lamlum, H., Lee, J., Massey, D., Miller, J. J. J. J., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.062021 · Cited by 129
Euglycemic diabetic ketoacidosis: etiologies, evaluation, and management
Long, B., Lentz, S., Koyfman, A., & Gottlieb, M. (2021) · The American Journal of Emergency Medicine · doi:10.1016/j.ajem.2021.02.015 · Cited by 150
Javed, Z., Papageorgiou, M., Deshmukh, H., Rigby, A. S., Qamar, U., Abbas, J., Khan, A. Y., Kilpatrick, E. S., Atkin, S. L., & Sathyapalan, T. (2019) · Clinical Endocrinology · doi:10.1111/cen.13968 · Cited by 121
Euglycemic Ketoacidosis as a Complication of SGLT2 Inhibitor Therapy
Palmer, B. F., & Clegg, D. J. (2021) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.17621120 · Cited by 134
“expenditure account for reductions in fat mass (19,20).”
BackgroundGlucose transporters in pancreatic islets
Berger, C., & Zdzieblo, D. (2020) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-020-02383-4 · Cited by 133
Kern, M., Klöting, N., Mark, M., Mayoux, E., Klein, T., & Blüher, M. (2015) · Metabolism · doi:10.1016/j.metabol.2015.10.010 · Cited by 117
“, the effect of empagliflozin on whole body metabolism was investigated in patients with T2D using clamp technology [25].”
BackgroundInfluentialEnergy balance and metabolic changes with sodium‐glucose co‐transporter 2 inhibition
Rajeev, S. P., Cuthbertson, D. J., & Wilding, J. P. H. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12578 · Cited by 117
“SGLT2 inhibition while having a stimulatory effect on glucagon [7,8,80], decreases insulin concentration [8], thus increasing the glucagon to insulin ratio.”
BackgroundInfluentialBonora, B. M., Avogaro, A., & Fadini, G. P. (2018) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13012 · Cited by 118
“lowering during SGLT2i therapy is associated with reduction in insulin concentrations, and SGLT2is can directly stimulate glucagon production by alpha cells.(12,13) The increased glucagon/insulin ratio,”
BackgroundUrine Metabolic Fingerprints Encode Subtypes of Kidney Diseases
Yang, J., Wang, R., Huang, L., Zhang, M., Niu, J., Bao, C., Shen, N., Dai, M., Guo, Q., Wang, Q., et al. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201913065 · Cited by 114
Scheen, A. J., & Paquot, N. (2014) · Diabetes & Metabolism · doi:10.1016/s1262-3636(14)72689-8 · Cited by 114
“plasma glucose concentrations (beta-cell glucose sensitivity) during a meal test [22].”
BackgroundMethodResultInfluentialBriand, F., Mayoux, E., Brousseau, E., Burr, N., Urbain, I., Costard, C., Mark, M., & Sulpice, T. (2016) · Diabetes · doi:10.2337/db16-0049 · Cited by 118
Perry, R. J., & Shulman, G. I. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.008387 · Cited by 121
“Indeed, hyperglucagonemia – which is a hallmark of diabetic ketoacidosis (47-49) – has been observed in both humans (50-52) and rodents (53-56) following treatment with an”
BackgroundLuna-Marco, C., Iannantuoni, F., Hermo-Argibay, A., Devos, D., Salazar, J. D., Víctor, V. M., & Rovira-Llopis, S. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.01.015 · Cited by 114
Anti-inflammatory effect of SGLT-2 inhibitors via uric acid and insulin
Grotta, R. L., de Candia, P., Olivieri, F., Matacchione, G., Giuliani, A., Rippo, M. R., Tagliabue, E., Mancino, M., Rispoli, F., Ferroni, S., et al. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04289-z · Cited by 121
“On the other hand, the effect of SGLT-2i on uric acid and insulin levels is very well documented by multiple studies [65, 66].”
BackgroundKullmann, S., Hummel, J., Wagner, R. J., Dannecker, C., Vosseler, A., Fritsche, L., Veit, R., Kantartzis, K., Machann, J., Birkenfeld, A. L., et al. (2021) · Diabetes Care · doi:10.2337/dc21-1136 · Cited by 112
“As most previous results have been obtained in patients with overt diabetes (17,18), a difference in the glycemic status might explain unaltered levels in our patients.”
BackgroundResultGarg, S. K., Peters, A. L., Buse, J. B., & Danne, T. (2018) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2018.0246 · Cited by 108
“21,22 SGLT2 inhibition also augments preproglucagon gene expression by acting directly on SGLT2 receptors in pancreatic alpha cells.”
Scheen, A. J. (2016) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2016.1215427 · Cited by 109
“to a significant rise in endogenous glucose production [18].”
BackgroundNishimura, R., Tanaka, Y., Koiwai, K., Inoue, K., Hach, T., Salsali, A., Lund, S. S., & Broedl, U. C. (2015) · Cardiovascular Diabetology · doi:10.1186/s12933-014-0169-9 · Cited by 109
Self-citationSGLT2 Inhibitors: Benefit/Risk Balance
Scheen, A. J. (2016) · Current Diabetes Reports · doi:10.1007/s11892-016-0789-4 · Cited by 110
Brown, E. E., Rajeev, S. P., Cuthbertson, D. J., & Wilding, J. P. H. (2019) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13650 · Cited by 107
“However, in the long term, other metabolic changes operate resulting in normalization of glucagon, glycogen as well as hepatic glucose production.(21) Nevertheless, this increment in endogenous glucose production may attenuate the glucose lowering efficacy of SGLT2i.”
BackgroundPerry, R. J., Rabin-Court, A., Song, J. D., CARDONE, R. L., Wang, Y., Kibbey, R. G., & Shulman, G. I. (2019) · Nature Communications · doi:10.1038/s41467-019-08466-w · Cited by 113
Wu, P., Wen, W., Li, J., Xu, J., Zhao, M., Chen, H., & Sun, J. M. (2019) · Hormone and Metabolic Research · doi:10.1055/a-0958-2441 · Cited by 111
“Recent studies have shown that use of SGLT2 inhibitor can improve the insulin resistance [29, 30], which could be explained by the decrease of glucose toxicity in response to induced urinary glucose ▶Fig.”
BackgroundState-of-the-Art-Review: Mechanisms of Action of SGLT2 Inhibitors and Clinical Implications
Vallon, V. (2024) · American Journal of Hypertension · doi:10.1093/ajh/hpae092 · Cited by 119
Sodium glucose cotransporter 2 inhibition in the diabetic kidney
Novikov, A., & Vallon, V. (2015) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000187 · Cited by 106
“blood glucose lowering agents, SGLT2 inhibition increased plasma glucagon concentrations and endogenous glucose production in T2DM db/db mice [25], diabetic TALLYHO/JngJ mice [25], insulin-resistant mice [20 && ], and in patients with T2DM [26,27].”
BackgroundDapagliflozin: A Review of Its Use in Patients with Type 2 Diabetes
Plosker, G. L. (2014) · Drugs · doi:10.1007/s40265-014-0324-3 · Cited by 108
“SGLT2 inhibitors also increase glucagon secretion, which in turn increases endogenous glucose production and may interfere with glucose control, as suggested in studies in patients with type 2 diabetes [18, 19] and from preclinical studies showing that SGLT2 inhibition triggers glucagon secretion in pancreatic alpha c…”
BackgroundSelvaraj, S., Fu, Z., Jones, P. G., Kwee, L. C., Windsor, S. L., Ilkayeva, O., Newgard, C. B., Margulies, K. B., Husain, M., Inzucchi, S. E., et al. (2022) · Circulation · doi:10.1161/circulationaha.122.060402 · Cited by 104
Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects
Kaplan, A., Abidi, E., EL‐Yazbi, A. F., Eid, A. H., Booz, G. W., & Zouein, F. A. (2018) · Heart Failure Reviews · doi:10.1007/s10741-017-9665-9 · Cited by 108
Empagliflozin Treatment Is Associated With Improved β-Cell Function in Type 2 Diabetes Mellitus
Jobori, H. A., Daniele, G., Adams, J. M., Cersósimo, E., Solis‐Herrera, C., Triplitt, C. L., DeFronzo, R. A., & Abdul-Ghani, M. A. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-01838 · Cited by 103
“Recent studies using oral glucose tolerance tests (OGTTs) have demonstrated that, in patients with T2DM, 2 to 4 weeks of dapagliflozin and empagliflozin treatment improved b-cell function (13, 14).”
BackgroundResultInfluentialOrtega, R., Collado, A., Selles, F., Navarro, H. G., Sanz, M., Real, J. T., & Piqueras, L. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.312659 · Cited by 102
“Ang II–infused apoE−/− mice were randomly allocated to the following groups: (1) treatment with vehicle (n=16), (2) treatment with empagliflozin at a dose of 1 mg/kg per day (n=16), and (3) treatment with empagliflozin at a dose of 3 mg/kg per day (n=16).”
MethodNewer Perspectives of Mechanisms for Euglycemic Diabetic Ketoacidosis
Yu, X., Zhang, S., & Zhang, L. (2018) · International Journal of Endocrinology · doi:10.1155/2018/7074868 · Cited by 102
“The hypoglycemic effect of this “carbohydrate deficit” is only partly offset by the increased endogenous glucose production (EGP) via gluconeogenesis and the decreased tissue glucose disposal (TGD) [31, 32].”
BackgroundMolecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection
Hou, Y., Zheng, C., Yen, T., & Lu, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217833 · Cited by 110
“Clinical trials on SGLT2i have revealed that hepatic endogenous glucose production increases as the plasma glucagon concentration increases [76,77].”
BackgroundJordan, J., Tank, J., Heusser, K., Heise, T., Wanner, C., Heer, M., Macha, S., Mattheus, M., Lund, S. S., Woerle, H. J., et al. (2017) · Journal of the American Society of Hypertension · doi:10.1016/j.jash.2017.07.005 · Cited by 102
Self-citationFioretto, P., Giaccari, A., & Sesti, G. (2015) · Cardiovascular Diabetology · doi:10.1186/s12933-015-0297-x · Cited by 104
“Evidence suggests that glycosuria induced by SGLT2 inhibitors can also significantly improve β-cell insulin secretion and insulin sensitivity in peripheral tissues, associated with a reduction in plasma glucose concentration [13, 14, 16, 17, 19].”
BackgroundSGLT inhibitors on weight and body mass: A meta‐analysis of 116 randomized‐controlled trials
Cheong, A. J. Y., Teo, Y. N., Teo, Y. H., Syn, N. L. X., Ong, H. T., Ting, A. Z. H., Chia, A. Z. Q., Chong, E. Y., Chan, M. Y., Lee, C., et al. (2021) · Obesity · doi:10.1002/oby.23331 · Cited by 107
“In addition, studies have posited that SGLT2 inhibitors indirectly improve β- cell function (9,10), likely in the process of glucotoxicity reversal (11).”
BackgroundSuga, T., Kikuchi, O., Kobayashi, M., Matsui, S., Yokota‐Hashimoto, H., Wada, E., Kohno, D., Sasaki, T., Takeuchi, K., Kakizaki, S., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.10.009 · Cited by 102
“Most previous evaluations of the effects of SGLT2 inhibitors on plasma glucagon levels were conducted with conventional RIA kits [12,13,19].”
BackgroundMethodWei, R., Cui, X., Feng, J. B., Gu, L., Lang, S., Wei, T., Yang, J., Liu, J., Le, Y., Wang, H., et al. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154324 · Cited by 102
Yabe, D., Nishikino, R., Kaneko, M., Iwasaki, M., & Seino, Y. (2015) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2015.1034105 · Cited by 96
Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice
Millar, P., Pathak, N., Parthsarathy, V., Bjourson, A. J., O’Kane, M., Pathak, V., Moffett, R. C., Flatt, P. R., & Gault, V. A. (2017) · Journal of Endocrinology · doi:10.1530/joe-17-0263 · Cited by 96
Colacci, M., Fralick, J., Odutayo, A., & Fralick, M. (2022) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2021.04.006 · Cited by 94
SGLT2 Inhibitors and Ketone Metabolism in Heart Failure
Saucedo‐Orozco, H., Voorrips, S. N., Yurista, S. R., de Boer, R. A., & Westenbrink, B. D. (2022) · Journal of Lipid and Atherosclerosis · doi:10.12997/jla.2022.11.1.1 · Cited by 101
SGLT2 Inhibitors and Mechanisms of Hypertension
Briasoulis, A., Al Dhaybi, O., & Bakris, G. L. (2018) · Current Cardiology Reports · doi:10.1007/s11886-018-0943-5 · Cited by 94
Yaribeygi, H., Sathyapalan, T., Maleki, M., Jamialahmadi, T., & Sahebkar, A. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.117090 · Cited by 95
“However, in addition to its anti-hyperglycemic effects through glycosuria, they may provide other beneficial effects such as suppression of gluconeogenesis, improving insulin sensitivity in peripheral tissues, increasing glucagon response and stimulation of insulin secretion from the beta cells of pancreatic islets [8…”
BackgroundCardiorenal diseases in type 2 diabetes mellitus: clinical trials and real-world practice
Lim, L.-L., Chow, E., & Chan, J. C. N. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00776-2 · Cited by 91
Cardiovascular Protection by Sodium Glucose Cotransporter 2 Inhibitors: Potential Mechanisms
Staels, B. (2017) · The American Journal of Medicine · doi:10.1016/j.amjmed.2017.04.009 · Cited by 97
“Additionally, a metabolic study in patients with T2DM confirmed that lowering elevated blood glucose levels with empagliflozin reduced glucose toxicity and improved b-cell function.(42) This study also demonstrated that insulin sensitivity of tissue glucose uptake was improved.”
BackgroundResultInfluentialThe Role of α-Cells in Islet Function and Glucose Homeostasis in Health and Type 2 Diabetes
Gilon, P. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.01.004 · Cited by 93
Inflammatory Trajectory of Type 2 Diabetes: Novel Opportunities for Early and Late Treatment
Pellegrini, V., Grotta, R. L., Carreras, F., Giuliani, A., Sabbatinelli, J., Olivieri, F., Berra, C., Ceriello, A., & Prattichizzo, F. (2024) · Cells · doi:10.3390/cells13191662 · Cited by 105
“This process triggers a systemic metabolic shift that encourages the use of ketones and fatty acids as alternative energy sources to glucose [181,182].”
BackgroundSodium‐glucose co‐transporter type‐2 inhibitors: pharmacology and peri‐operative considerations
Milder, D. A., Milder, T. Y., & Kam, P. C. A. (2018) · Anaesthesia · doi:10.1111/anae.14251 · Cited by 93
“and this results in increased lipolysis and fatty acid oxidation in the liver as well as hepatic ketogenesis [7, 34].”
BackgroundErion, D. M., Park, H., & Lee, H. (2016) · BMB Reports · doi:10.5483/bmbrep.2016.49.3.268 · Cited by 89
“In the clinical setting, SGLT2 inhibition was shown to cause a modest reduction in body weight and blood pressure, although there were increases in circulating LDL concentrations (69, 70).”
BackgroundInfluentialAge-related diseases as vicious cycles
Belikov, A. V. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.11.002 · Cited by 95
Safety and Tolerability of Empagliflozin in Patients with Type 2 Diabetes
Köhler, S., Salsali, A., Hantel, S., Kaspers, S., Woerle, H. J., Kim, G., & Broedl, U. C. (2016) · Clinical Therapeutics · doi:10.1016/j.clinthera.2016.03.031 · Cited by 90
Self-citationSGLT2 Inhibitors: Nephroprotective Efficacy and Side Effects
Garofalo, C., Borrelli, S., Liberti, M., Andreucci, M., Conte, G., Minutolo, R., Provenzano, M., & Nicola, L. D. (2019) · Medicina · doi:10.3390/medicina55060268 · Cited by 95
“In addition, a main determinant is the SGLT2-i related-hyperglucagonemia that per se increases the propensity toward ketone production [32,33,67].”
BackgroundMiller, S. S., Krumins, T., Zhou, H., Huyck, S. B., Johnson, J. R., Golm, G. T., Terra, S. G., Mancuso, J. P., Engel, S. S., & Lauring, B. P. (2018) · Diabetes Therapy · doi:10.1007/s13300-017-0358-0 · Cited by 88
“Recent small mechanistic studies have suggested that SGLT2 inhibition may lead to increased insulin sensitivity and improved bcell function [31, 32].”
BackgroundWhat does sodium‐glucose co‐transporter 1 inhibition add: Prospects for dual inhibition
Rieg, J. A. D., & Rieg, T. (2019) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13630 · Cited by 90
Peters, A. L., Henry, R. R., Thakkar, P., Tong, C., & Alba, M. (2016) · Diabetes Care · doi:10.2337/dc15-1995 · Cited by 106
Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond
Martens, P., Mathieu, C., & Verbrugge, F. H. (2017) · Current Treatment Options in Cardiovascular Medicine · doi:10.1007/s11936-017-0522-x · Cited by 88
Yabe, D., Shiki, K., Homma, G., Meinicke, T. W., Ogura, Y., Seino, Y., & EMPA‐ELDERLY Investigators (2023) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15249 · Cited by 93
Packer, M. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvaa064 · Cited by 86
Min, S. H., Yoon, J., Hahn, S., & Cho, Y. M. (2016) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2818 · Cited by 87
Canagliflozin: A Review of Its Use in Patients with Type 2 Diabetes Mellitus
Plosker, G. L. (2014) · Drugs · doi:10.1007/s40265-014-0225-5 · Cited by 85
“In addition, the observed bodyweight loss from SGLT2 inhibitors is lower than that expected from sustained energy loss via increased glucosuria, which may be a consequence of compensatory hyperphagia (as suggested in a rat model [49]) and/or increased endogenous glucose production resulting from increased glucagon sec…”
BackgroundEmpagliflozin as add‐on to metformin in people with Type 2 diabetes
Merker, L., Häring, H.-U., Christiansen, A. V., Roux, F., Salsali, A., Kim, G.-H., Meinicke, T. W., Woerle, H. J., Broedl, U. C., & the EMPA‐REG EXTEND MET investigators (2015) · Diabetic Medicine · doi:10.1111/dme.12814 · Cited by 83
Self-citationPetito‐da‐Silva, T. I., Souza‐Mello, V., & Barbosa‐da‐Silva, S. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2019.110539 · Cited by 82
Kashiwagi, A., & Maegawa, H. (2017) · Journal of Diabetes Investigation · doi:10.1111/jdi.12644 · Cited by 80
“IMPROVEMENTS IN INSULIN SECRETION, INSULIN SENSITIVITY AND GLUCOSE TOXICITY WITH ENHANCED GLUCAGON SECRETION Ferrannini et al.(36) measured whole-body glucose utilization using the double-tracer glucose administration method after single-dose and chronic empagliflozin 25 mg once daily for 4 weeks compared with baselin…”
MethodKaneto, H., Obata, A., Kimura, T., Shimoda, M., Okauchi, S., Shimo, N., Matsuoka, T., & Kaku, K. (2016) · Journal of Diabetes · doi:10.1111/1753-0407.12494 · Cited by 80
“It has also been reported that endogenous glucose production is increased in subjects with T2D after 4 weeks treatment with empagliflozin, which was also accompanied by increases in glucagon levels.(45) We do not think that increased hepatic glucose production indicates aggravation of insulin resistance in the liver;…”
BackgroundThe Pleiotropic Effects of Sodium–Glucose Cotransporter-2 Inhibitors: Beyond the Glycemic Benefit
Patel, D. K., & Strong, J. L. (2019) · Diabetes Therapy · doi:10.1007/s13300-019-00686-z · Cited by 83
Immunomodulatory Effects of SGLT2 Inhibitors—Targeting Inflammation and Oxidative Stress in Aging
Schönberger, E., Mihaljević, V., Steiner, K., Šarić, S., Kurevija, T., Majnarić, L. T., Bilić-Čurčić, I., & Canecki-Varžić, S. (2023) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph20176671 · Cited by 87
Therapeutic medications against diabetes: What we have and what we expect
Hu, C., & Jia, W. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.11.008 · Cited by 81
Insulin Resistance the Link between T2DM and CVD: Basic Mechanisms and Clinical Implications
Abdul‐Ghani, M. A., Jayyousi, A., DeFronzo, R. A., Asaad, N., & Suwaidi, J. M. S. A. (2017) · Current Vascular Pharmacology · doi:10.2174/1570161115666171010115119 · Cited by 79
SGLT2 inhibitors and lower limb complications: an updated meta‐analysis
Lin, C., Zhu, X., Cai, X., Yang, W., Lv, F., Nie, L., & Ji, L. (2021) · Cardiovascular Diabetology · doi:10.1186/s12933-021-01276-9 · Cited by 80
“When excess body fluid was excreted and a dry body weight was reached, SGLT2i continued to reduce or maintain the body weight by urinary glucose excretion and additional regulatory effects on metabolism [14], which might play greater role in the later phase of weight reduction.”
BackgroundGlucagon and heart in type 2 diabetes: new perspectives
Ceriello, A., Genovese, S., Mannucci, E., & Gronda, E. (2016) · Cardiovascular Diabetology · doi:10.1186/s12933-016-0440-3 · Cited by 79
“Also, DPP4i increase insulin secretion and decrease glucagon; so, potentially they block the compensatory EGP seen with SGLT-2i and increase their glucose-lowering capacity [38, 41, 42].”
BackgroundBaker, H. E., Kiel, A. M., Luebbe, S. T., Simon, B. R., Earl, C. C., Regmi, A., Roell, W. C., Mather, K. J., Tune, J. D., & Goodwill, A. G. (2019) · Basic Research in Cardiology · doi:10.1007/s00395-019-0733-2 · Cited by 77
Herbert, T. P., & Laybutt, D. R. (2016) · Diabetes · doi:10.2337/db15-1633 · Cited by 72
Wallenius, K., Kroon, T., Hagstedt, T., Löfgren, L., Sörhede‐Winzell, M., Boucher, J., Lindén, D., & Oakes, N. D. (2022) · Journal of Lipid Research · doi:10.1016/j.jlr.2022.100176 · Cited by 77
“in patients with type 2 diabetes (24, 27, 28), this does not”
BackgroundResult
Metadata
- Authors
- Ferrannini, E., Muscelli, E., Frascerra, S., Baldi, S., Mari, A., Heise, T., Broedl, U. C., & Woerle, H.-J.
- Affiliations
- University of Pisa (IT)
- National Research Council (IT)
- Profil Institute for Metabolic Research (DE)
- Boehringer Ingelheim (Germany) (DE)
- Corresponding author
- Ferrannini, Ele
- Venue
- Journal of Clinical Investigation
- Published
- 2014-01-27
- Volume
- 124
- Issue
- 2
- Pages
- 499-508
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3904627
- OpenAlex
- W2157405334
- Cited by
- 1,134
- References
- 45
- Citations by year
- 2026: 55 · 2025: 68 · 2024: 80 · 2023: 81 · 2022: 92 · 2021: 117 · 2020: 106 · 2019: 103 · 2018: 97 · 2017: 90 · 2016: 121 · 2015: 83 · 2014: 39
- FWCI
- 89.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- American Diabetes Association
- Bristol-Myers Squibb
- Eli Lilly and Company
- AstraZeneca
- Sanofi
- Novo Nordisk
- Astellas Pharma
- Daiichi Sankyo Europe
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SGLT2 inhibitors, empagliflozin, type 2 diabetes, glycosuria, endogenous glucose production, glucose oxidation, nonoxidative glucose disposal, lipid oxidation, beta-cell glucose sensitivity, glucagon response, insulin response, glucose metabolism, indirect calorimetry, mixed meal tolerance, urinary glucose excretion, glucose homeostasis
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Aged, Benzhydryl Compounds, Blood Glucose, Calorimetry, Diabetes Mellitus, Type 2, Female, Glucose, Glucosides, Glycosuria, Glycated Hemoglobin, Humans, Insulin, Male, Metformin, Middle Aged, Oxygen, Body Mass Index, Postprandial Period, Area Under Curve, Insulin-Secreting Cells, Sodium-Glucose Transporter 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
